: Abnormalities of telecephalic development have been implicated in the etiology of psychiatric illnesses such as autism and schizophrenia. Previous studies have indicated that different telecephalic regions, including the basal ganglia and neocortex, are derived from spatially distinct proliferative zones. However, recent evidence suggests that a population of neocortical neurons originates within the ventral (subcortical) telencephalon in the primordia of the basal ganglia (Anderson et al., in press). The purpose of this proposal is to further investigate what types of neocortical cells originate in the subcortical telencephalon, where they originate within this region, and what are the mechanisms of this migration. Several approaches will be used, including the analysis of mutant mice lacking this migration and the injection of cell tracers into embryonic ferrets in vivo. In addition, mechanistic characteristics of subcortical to neocortical migration will be studied by combining slice culture experiments with electron microscopy and by testing the hypothesis that chemotaxant factors guide cellular migration from the subcortical telencephalon into the neocortex. The candidate is a psychiatrist with a long-standing interest in the biology of neuropsychiatric disorders. As a postdoctoral fellow, he has spent three years in the laboratory of John Rubenstein at UCSF examining the molecular genetic underpinnings of forebrain development. Short-term goals are to remain in this laboratory as an adjunct assistant professor to further develop basic research skills at the organ, cellular, and molecular levels. Through collaborations with three other laboratories, those of Peter Ralston and Marc Tessier-Lavigne at UCSF and Susan McConnell at Stanford University, this project will involve a significant broadening of research experience. In addition, the candidate is committed to enhancing clinical skills with a focus on psychotic disorders. These goals will be attained through a program which devotes 75-80% time to research and no more than 25% time to clinical work and teaching. The candidate's long-term goal is to establish an independent academic career studying neuronal migration and differentiation in the mammalian telencephalon. It is hoped this work will contribute to the investigation of abnormal brain development as it occurs in human neurodevelopmental disorders.